Melt-extruded orally administrable opioid formulations

ABSTRACT

Bioavailable sustained release oral opioid analgesic dosage forms, comprising a plurality of multiparticulates produced via melt extrusion techniques are disclosed.

BACKGROUND OF THE INVENTION

The present invention relates to the use of melt extrusion technology inthe production of bioavailable sustained-release matrix pharmaceuticalformulations. Previously, melt extrusion has been used in the productionof immediate release formulations.

It is known in the pharmaceutical art to prepare compositions whichprovide for controlled release of pharmacologically active substancescontained in the compositions after oral administration to humans andanimals. Such slow release compositions are used to delay absorption ofa medicament until it has reached certain portions of the alimentarytract. Such sustained-release of a medicament in the alimentary tractfurther maintains a desired concentration of said medicament in theblood stream for a longer duration than would occur if conventionalrapid release dosage forms are administered.

Different methods of preparing controlled release pharmaceutical dosageforms have been suggested. For example, direct compression techniques,wet granulation techniques, encapsulation techniques and the like havebeen proposed to deliver pharmaceutically active ingredients to thealimentary tract over extended periods.

Additionally, various types of sustained release formulations are knownin the art, including specially coated tablets, coated tablets andcapsules wherein the slow release of the active medicament is broughtabout through selective breakdown of the coating of the preparation orthrough compounding with a special matrix to affect the release of adrug. Some sustained release formulations provide for related sequentialrelease of a single dose of an active compound at predetermined periodsafter administration.

It is the intent of all sustained-release preparations to provide alonger period of pharmacologic response after the administration of thedrug and is ordinarily experienced after the administration of the rapidrelease dosage forms. Such longer periods of response provide for manyinherent therapeutic benefits that are not achieved with correspondingshort acting, immediate release preparations. This is especially true inthe treatment of cancer patients or other patients in need of treatmentfor the alleviation of moderate to severe pain, where blood levels of anopioid analgesic medicament must be maintained at a therapeuticallyeffective level to provide pain relief. Unless conventional rapid actingdrug therapy is carefully administered at frequent intervals to maintaineffective steady state blood levels of the drug, peaks and valleys inthe blood level of the active drug occur because of the rapidabsorption, systemic excretion of the compound and through metabolicinactivation, thereby producing special problems maintenance ofanalgesic efficacy.

The prior art teaching of the preparation and use of compositionsproviding the sustained-release of an active compound from a carrier isbasically concerned with the release of the active substance into thephysiologic fluid of the alimentary tract. However, it is generallyrecognized that the mere presence of an active substance in thegastrointestinal fluids does not, by itself, insure bioavailability.

In order to be absorbed, the active drug substance must be in solution.The time required for a given proportion of an active substance from aunit dosage form is determined as the proportion of the amount of activedrug substance released from a unit dosage form over a specified timebase by a test method conducted under standardized conditions. Thephysiologic fluids of the gastrointestinal tract are the media fordetermining dissolution time. The present state of the art recognizesmany satisfactory test procedures to measure dissolution time forpharmaceutical compositions, and these test procedures are described inofficial compendia world wide.

Although there are many diverse factors which influence the dissolutionof drug substance from its carrier, the dissolution time determined fora pharmacologically active substance from the specific composition isrelatively constant and reproducible. Among the different factorsaffecting the dissolution time are the surface area of the drugsubstance presented to the dissolution solvent medium, the pH of thesolution, the solubility of the substance in the specific solventmedium, and the driving forces of the saturation concentration ofdissolved materials in the solvent medium. Thus, the dissolutionconcentration of an active drug substance is dynamically modified in itssteady state as components are removed from the dissolution mediumthrough absorption across the tissue site. Under physiologic conditions,the saturation level of the dissolved materials is replenished from thedosage form reserve to maintain a relatively uniform and constantdissolution concentration in the solvent medium providing for a steadystate absorption.

The transport across a tissue absorption site of the gastrointestinaltract is influenced by the Donnan osmotic equilibrium forces on bothsides of the membrane since the direction of the driving force is thedifference between the concentrations of active substance on either sideof the membrane, i.e., the amount dissolved in the gastrointestinalfluids and the amount present in the blood. Since the blood levels areconstantly being modified by dilution, circulatory changes, tissuestorage, metabolic conversion and systemic excretion, the flow of activematerials is directed from the gastrointestinal tract into the bloodstream.

Notwithstanding the diverse factors influencing both dissolution andabsorption of a drug substance, a strong correlation has beenestablished between the in-vitro dissolution time determined for adosage form and (in-vivo) bioavailability. The dissolution time and thebioavailability determined for a composition are two of the mostsignificant fundamental characteristics for consideration whenevaluating sustained-release compositions.

Melt granulation techniques have also been suggested to providecontrolled release formulations. Generally, melt granulation involvesmechanically working an active ingredient in particulate form with oneor more suitable binders and/or pharmaceutically acceptable excipientsin a mixer until one or more of the binders melts and adheres to thesurface of the particulate, eventually building up granules.

U.S. Pat. No. 4,957,681 (Klimesch), et. al.) discloses a continuousprocess for preparing pharmaceutical mixtures having at least twocomponents which are continuously metered. The process includescontinuously metering the individual components of the pharmaceuticalmixture at a rate of at least 50 g/h on electronic differential meteringbalances having a metering accuracy of at least ±5% within timeintervals of less than one minute and, additionally, having screwconveyors, thereby obtaining a substantially uniformly metered mixture;and shaping the mixture. Example 1 of the '681 patent is representativeof the process. The requisite amounts of a copolymer having a K value of30 and obtained from 60% of N-vinylpyrrolid-2-one (NVP), stearyl alcoholand theophylline are metered via three metering balances into the hopperof an extruder and extruded. The temperatures of the extruder cylinderconsisting of six shots ranged from 30-60° C. and the die is heated to100° C. The resultant extrudate is then pressed into tablets of therequired shape. The '681 patent does not disclose preparation ofsustained release opioid pharmaceutical formulations.

N. Follonier., et al., Hot-Melt Extruded Pellets for the SustainedRelease of Highly Dosed Freely Soluble Drugs, Proceed. Intern. Symp.Control. Rel. Bioact. Mater., 18 (1991) describes certain diltiazemhydrochloride formulations prepared using hot-melt screw-extrusion toobtain sustained-release pellets to be filled into hard gelatincapsules. The polymers used were ethylcellulose, a copolymer of ethylacrylate and methyl methacrylate containing quaternary ammonium groups,cellulose acetate butyrate, poly(vinyl chloride-co-vinyl acetate) and acopolymer of ethylene and vinyl acetate. In order to lower the extrusiontemperature, some plasticizers were used.

WO 93/07859 describes drug loaded pellets produced through meltspheronization wherein the therapeutically active agent is blended withvarious excipoients and binders; the formulation is fed to an extruderwhere it is heated and extruded at a speed of about 0.05 to 10 mm/sec.at approximately 60-180° C. The extrudate is then cut into pieces in apelletizer and subsequently fed to a spheronizer for uniform pelletformation.

Despite the foregoing advances and the various techniques for preparingsustained release formulations available in the pharmaceutical art,there is a need in the art for an orally administrable opioidformulation which would provide an extended duration of effect which isalso easy to prepare, e.g via melt-granulation techniques.

OBJECTS AND SUMMARY OF THE INVENTION

It is therefore an object of the present invention to providesustained-release pharmaceutical formulations suitable for oraladministration and methods for preparing the same utilizingmelt-extrusion techniques.

It is also an object of the present invention to provide improvedmethods for producing pharmaceutical extrudates containing opioidanalgesics and pharmaceutical acceptable hydrophobic materials via meltextrusion techniques.

It is a further object of the present invention to provide asustained-release melt extruded multi-particulate formulation which neednot be spheronized in order to obtain a final dosage form.

It is also an object of the present invention to provide methods oftreatment for human patients in need of opioid analgesic therapy usingdosage forms prepared in accordance with the methods disclosed herein.

In accordance with the above objects and others which will be apparentfrom the further reading of the specification and of the appendedclaims, the present invention is related in part to the surprisingdiscovery that sustained-release oral opioid analgesic formulations maybe prepared utilizing melt extrusion techniques to provide bioavailableunit dose products which provide analgesia in a patient for, e.g., 8-24hours.

The invention is also related in part to a new melt-extruded oralsustained-release dosage forms which comprise a pharmaceuticallyacceptable hydrophobic material, a retardant selected from waxes, fattyalcohols, and fatty acids, and a drug.

More particularly, one aspect of the present invention is related to apharmaceutical extrudate including an opioid analgesic dispersed in amatrix. Preferably, the extrudate is strand or spaghetti-shaped and hasa diameter from about 0.1 to about 5 mm. The extrudate is divided intounit doses of the opioid analgesic for oral administration to a patient,and provides a sustained analgetic effect for 8-24 hours or more.

The matrices preferably include a hydrophobic material and a secondretardant material (preferably a hydrophobic fusible carrier) which actsto further slow or control the release of the therapeutically activeagent when the formulation is exposed to aqueous solutions in-vitro, orexposed to gastic and/or intestinal fluids.

Preferably, the hydrophobic material is selected from the groupconsisting of alkylcelluloses, acrylic and methacrylic acid polymers andcopolymers, shellac, zein, hydrogenated castor oil or hydrogenatedvegetable oil, or mixtures thereof.

The retardant material (hydrophobic fusible carrier) is preferablyselected from natural and synthetic waxes, fatty acids, fatty alcoholsand mixtures of the same. Examples include beeswax and carnauba wax,stearic acid, and stearyl alcohol). This list is of course not meant tobe exclusive.

The extrudate may be cut into multiparticulates by any cutting meansknown in the art. Preferably, the multiparticulates have a length offrom about 0.1 to 5 mm in length. The multiparticulates may then bedivided into unit doses such that each individual unit dose includes adose of opioid analgesic sufficient to provide analgesia to a mammal,preferably a human patient.

The unit doses of multiparticulates may then be incorporated into asolid pharmaceutical dosage formulation, e.g. via compression or shapinginto tablets, by placing a requisite amount inside a gelatin capsule, orby forming the extruded product into the form of a suppository.

The pharmaceutical extrudates of the present invention may be preparedby blending the drug together with all matrix ingredients (hydrophobicmaterial, binder and any additional (optional) excipients), feeding theresultant mixture into an extruder heated to the requisite temperaturenecessary to soften the mixture sufficiently to render the mixtureextrudable; extruding the viscous, heated mass as a spaghetti-likestrand; allowing the extrudate to congeal and harden, and then dividingthe strand into desired pieces. This may be accomplished, e.g., bycutting the strands into pellets of 1.5 mm diameter and 1.5 mm inlength. Preferably, the extrudate has a diameter of from about 0.1 toabout 5 mm and provides sustained release of said opioid analgesic for atime period of from about 8 to about 24 hours.

Another aspect of the invention is directed to pharmaceutical dosageforms including the extrudate prepared as outlined above. The extrudateis cut into multiparticulates using any cutting means known in the art,e.g a blade. The multiparticulates are then divided into unit dosescontaining an effective amount of opioid analgesic to provide analgesiaor pain relief in a human patient over the desired dosing interval. Theunit dose of multiparticulates may then be incorporated into tablets,e.g. via direct compression, formed into suppositories, or encapsulatedby any means known in the art.

In yet a further aspect of the invention, there is provided a method oftreating a patient with sustained-release formulations prepared asdescribed above. This method includes administering a dosage formcontaining the novel extrudate to a patient in need of opioid analgesictherapy. For purposes of the present invention, a unit dose isunderstood to contain an effective amount of the therapeutically activeagent to produce pain relief and/or analgesia to the patient. Oneskilled in the art will recognize that the dose of opioid analgesicadministered to a patient will vary due to numerous factors; e.g. thespecific opioid analgesic(s) being administered, the weight andtolerance of the patient, other therapeutic agents concomitantly beingadministered, etc.

As mentioned above, in order for a dosage form to be effective for itsintended purpose, the dosage form must be bioavailable. For purposes ofthe present invention, the term “bioavailable” is defined as the totalamount of a drug substance that is absorbed and available to provide thedesired therapeutic effect after administration of a unit dosage form.Generally, the bioavailability of a given dosage form is determined bycomparison to a known reference drug product, as commonly determined andaccepted by Governmental Regulatory Agencies, such as the United StatesFDA.

The term “bioavailability” is defined for purposes of the presentinvention as the extent to which the drug (e.g., opioid analgesic) isabsorbed from the unit dosage form and is available at the site of drugaction.

The terms “sustained release”, “extended duration”, and “controlledrelease” are defined for purposes of the present invention as therelease of the drug (e.g., opioid analgesic) at such a rate that blood(e.g., plasma) levels are maintained within the therapeutic range butbelow toxic levels over a period of time greater than 8 hours, morepreferably for about 12 to about 24 hours, or longer.

The term “unit dose” is defined for purposes of the present invention asthe total amount of multiparticulates needed to administer a desireddose of therapeutically active agent (e.g., opioid analgesic) to apatient.

The extrudates of the present invention preferably permit release of theopioid (or salts thereof) over a sustained period of time in an aqueousmedium. The term “Aqueous medium” is defined for purposes of the presentinvention as any water-containing medium, e.g. water, pharmaceuticallyacceptable dissolution medium, gastric fluid and/or intestinal fluid andthe like.

BRIEF DESCRIPTION OF THE DRAWINGS

The following drawing is illustrative of an embodiment of the inventionand is not meant to limit the scope of the invention as encompassed bythe claims.

FIG. 1 is a graph displaying the dissolution results of Examples 1 and2;

FIG. 2 is a graph displaying the dissolution rates of Examples 3-6;

FIGS. 3 and 4 are graphs displaying the pH dependency of the dissolutionresults of Examples 3 and 6 respectively;

FIG. 5 is a graph displaying the dissolution results of Examples 7 and 8vs. Example 6;

FIG. 6 is a graph displaying the dissolution results of Examples 9 and10;

FIG. 7 is a graph displaying the dissolution results of Examples 11 and12;

FIG. 8 is a graph displaying the dissolution results of Examples 15 and16;

FIG. 9 is a schematic representation of a system for carrying out thepresent invention;

FIG. 10 is a graph displaying the fed/fast bioavailability results forExample 20;

FIG. 11 is a graph displaying the plasma morphine concentrations ofExample 21 obtained from administration of the capsules from Example 6vs. MS Contin®;

FIG. 12 is a graph displaying the plasma oxycodone concentrations ofExamples 22 obtained from administrating the capsules from Examples 11and 13 vs. OxyContin®;

FIG. 13 is a graphical representation of the plasma oxycodoneconcentrations of Example 14;

FIG. 14 is a graphical representation of the hydromorphoneconcentrations of Example 24 using the capsules from Example 17 vs.Dilaudud®;

FIG. 15 is a graph displaying the plasma hydromorphone concentrations ofExample 24 using capsules from Example 18 vs. Dilaudud®;

FIG. 16 is a graph of the steady-state plasma hydromorphoneconcentrations of Example 25 using the capsules of Example 17; and

FIG. 17 is a graph of the plasma hydromorphone concentrations of Example26 using the capsules of Example 19.

DETAILED DESCRIPTION

In one aspect of the invention, the sustained-release dosage formscomprise an opioid analgesic as the therapeutically active agent. Insuch formulations, the drug is incorporated into a melt-extruded strandwhich includes a pharmaceutically acceptable hydrophobic material suchas an alkylcellulose or an acrylic polymer or copolymer. In certainembodiments, it is preferably to further add to the blend a plasticizerfor the hydrophobic material in order to reduce the extrusiontemperature. The choice of the most suitable plasticizer is made basedon its ability to lower the glass transition temperature (Tg) of thepolymer. In preferred alternative embodiments, a hydrophobic fusiblecarrier (which may also act as a binder) is utilized instead of aplasticizer. The hydrophobic fusible carrier preferably imparts a slowerrelease of the therapeutically active agent from the melt extrudedformulation. Any further pharmaceutical excipients known to thoseskilled in the art may be added as deemed necessary.

Another aspect of the invention is directed to improved melt extrudedmatrices which comprise a hydrophobic material and a fatty binder suchas previously specified. In accordance therewith, a therapeuticallyactive agent is combined with one or more suitable hydrophobic materialsand a hydrophobic fusible carrier is extruded to form an extrudate. Theextrudate may then be cut into multiparticulates which are subsequentlyincorporated into sustained release dosage forms.

Therapeutically Active Agents

Therapeutically active agents which may be used in accordance with thepresent invention include both water soluble and water insoluble drugs.Examples of such therapeutically active agents include antihistamines(e.g., dimenhydrinate, diphenhydramine, chlorpheniramine anddexachlorpheniramine maleate), analgesics (e.g., aspirin, codeine,morphine, dihydromorphone, oxycodone, etc.), non-steroidalanti-inflammatory agents (e.g., naproxen, diclofenac, indomethacin,ibuprofen, sulindac), anti-emetics (e.g., metoclopramide,methylnaltrexone), anti-epileptics (e.g., phenytoin, meprobamate andnitrazepam), vasodilators (e.g., nifedipine, papaverine, diltiazem andnicardipine), anti-tussive agents and expectorants (e.g., codeinephosphate), anti-asthmatics (e.g. theophylline), antacids,anti-spasmodics (e.g. atropine, scopolamine), antidiabetics (e.g.,insulin), diuretics (e.g., ethcrynic acid, bendrofluthiazide),anti-hypotensives (e.g., propranolol, clonidine), antihypertensives(e.g, clonidine, methyldopa), bronchodilators (e.g., albuterol),steroids (e.g., hydrocortisone, triamicinolone, prednisone), antibiotics(e.g., tetracycline), antihemorrhoidals, hypnotics, psychotropics,antidiarrheals, mucolytics, sedatives, decongestants, laxatives,vitamins, stimulants (including appetite suppressants such asphenylpropanolamine), as well as salts, hydrates, and solvates of thesame.

In embodiments of the invention directed to opioid analgesics, theopioid analgesics used in accordance with the present invention includealfentanil, allylprodine, alphaprodine, anileridine, benzylmorphine,bezitramide, buprenorphine, butorphanol, clonitazene, codeine,cyclazocine, desomorphine, dextromoramide, dezocine, diampromide,dihydrocodeine, dihydromorphine, dimenoxadol, dimepheptanol,dimethylthiambutene, dioxaphetyl butyrate, dipipanone, eptazocine,ethoheptazine, ethylmethylthiambutene, ethylmorphine, etonitazenefentanyl, heroin, hydrocodone, hydromorphone, hydroxypethidine,isomethadone, ketobemidone, levallorphan, levorphanol,levophenacylmorphan, lofentanil, meperidine, meptazinol, metazocine,methadone, metopon, morphine, myrophine, nalbuphine, narceine,nicomorphine, norlevorphanol, normethadone, nalorphine, normorphine,norpipanone, opium, oxycodone, oxymorphone, papaveretum, pentazocine,phenadoxone, phenomorphan, phenazocine, phenoperidine, piminodine,piritramide, propheptazine, promedol, properidine, propiram,propoxyphene, sufentanil, tramadol, tilidine, salts thereof, mixtures ofany of the foregoing, mixed mu-agonists/antagonists, mu-antagonistcombinations, and the like. The opioid analgesic may be in the form ofthe free base, or in the form of a pharmaceutically acceptable salt, orin the form of a pharmaceutically acceptable complex.

In certain preferred embodiments, the opioid analgesic is selected frommorphine, codeine, hydromorphone, hydrocodone, oxycodone,dihydrocodeine, dihydromorphine, oxymorphone, tramadol or mixturesthereof.

In one preferred embodiment the sustained-release opioid oral dosageform of the present invention includes hydromorphone as thetherapeutically active ingredient in an amount from about 4 to about 64mg hydromorphone hydrochloride. Alternatively, the dosage form maycontain molar equivalent amounts of other hydromorphone salts or of thehydromorphone base. In other preferred embodiments where the opioidanalgesic is other than hydromorphone, the dosage form contains anappropriate amount to provide a substantially equivalent therapeuticeffect. For example, when the opioid analgesic comprises morphine, thesustained-release oral dosage forms of the present invention includefrom about 5 mg to about 800 mg morphine, by weight (based on morphinesulfate). When the opioid analgesic comprises oxycodone, thesustained-release oral dosage forms of the present invention includefrom about 5 mg to about 400 mg oxycodone. When the opioid analgesic istramadol, the sustained-release oral dosage forms of the inventioninclude from about 50 mg to about 800 mg tramadol by weight, based onthe hydrochloride salt.

The sustained-release dosage forms of the present invention generallyachieve and maintain therapeutic levels substantially withoutsignificant increases in the intensity and/or degree of concurrent sideeffects, such as nausea, vomiting or drowsiness, which are oftenassociated with high blood levels of opioid analgesics. There is alsoevidence to suggest that the use of the present dosage forms leads to areduced risk of drug addiction.

In the present invention, the oral opioid analgesics have beenformulated to provide for an increased duration of analgesic.Surprisingly, these formulations, at comparable daily dosages ofconventional immediate-release drug, are associated with a lowerincidence in severity of adverse drug reactions and can also beadministered at a lower daily dose than conventional oral medicationwhile maintaining pain control.

When the therapeutically active agent included in the dosage forms ofthe present invention is an opioid analgesic, the dosage form mayfurther include one or more additional which may or may not actsynergistically with the opioid analgesics of the present invention.Examples of such additional therapeutically active agents includenon-steroidal anti-inflammatory agents, including ibuprofen, diclofenac,naproxen, benoxaprofen, flurbiprofen, fenoprofen, flubufen, ketoprofen,indoprofen, piroprofen, carprofen, oxaprozin, pramoprofen, muroprofen,trioxaprofen, suprofen, aminoprofen, tiaprofenic acid, fluprofen,bucloxic acid, indomethacin, sulindac, tolmetin, zomepirac, tiopinac,zidometacin, acemetacin, fentiazac, clidanac, oxpinac, mefenamic acid,meclofenamic acid, flufenamic acid, niflumic acid tolfenamic acid,diflurisal, flufenisal, piroxicam, sudoxicam or isoxicam, and the like.Other suitable additional drugs which may be included in the dosageforms of the present invention include acetaminophen, aspirin,salicylate-derived analgesics and antipyretics or salts thereof, andother non-opioid analgesics.

The additional (non-opioid) therapeutically active agent may be includedin controlled release form or in immediate release form. The additionaldrug may be incorporated into the controlled release matrix along withthe opioid; incorporated as a separated controlled release layer orimmediate release layer; or may be incorporated as a powder,granulation, etc., in a gelatin capsule with the extrudates of thepresent invention.

Matrix Ingredients

The extrudates of the present invention include at least one hydrophobicmaterial. The hydrophobic material will preferably impart sustainedrelease of the opioid analgesic to the final formulation. Preferredhydrophobic materials which may be used in accordance with the presentinvention include alkylcelluloses such as natural or syntheticcelluloses derivatives (e.g. ethylcellulose), acrylic and methacrylicacid polymers and copolymers, shellac, zein, wax-type substancesincluding hydrogenated castor oil or hydrogenated vegetable oil, ormixtures thereof. This list is not meant to be exclusive, and anypharmaceutically acceptable hydrophobic material which is capable ofimparting sustained release of the active agent and which melts (orsoftens to the extent necessary to be extruded) may be used inaccordance with the present invention.

In certain preferred embodients of the present invention, thehydrophobic material is a pharmaceutically acceptable acrylic polymer,including but not limited to acrylic acid and methacrylic acidcopolymers, methyl methacrylate, methyl methacrylate copolymers,ethoxyethyl methacrylates, cyanoethyl methacrylate, aminoalkylmethacrylate copolymer, poly(acrylic acid), poly(methacrylic acid),methacrylic acid alkylamine copolymer, poly(methyl methacrylate),poly(methacrylic acid)(anhydride), polymethacrylate, polyacrylamide,poly(methacrylic acid anhydride), and glycidyl methacrylate copolymers.In other embodiments, the hydrophobic material is selected from materilssuch as hydroxyalkylcelluoses such as hydroxypropylmethylcellulose andmixtures of the foregoing.

The retardant material is preferably a hydrophobic fusible carrier whichmay comprise one or more water-insoluble wax-like thermoplasticsubstances possibly mixed with one or more wax-like thermoplasticsubstances being less hydrophobic than said one or more water-insolublewax-like substances. In order to achieve constant release, theindividual wax-like substances in the binder material should besubstantially non-degradable and insoluble in gastrointestinal fluidsduring the initial release phases.

Useful water-insoluble wax-like substances may be those with awater-solubility that is lower than about 1:5,000 (w/w).

Such hydrophobic fusible carrier materials are preferablywater-insoluble with more or less pronounced hydrophilic and/orhydrophobic trends. Preferably, the retardant materials useful in theinvention have a melting point from about 30 to about 200° C.,preferably from about 45 to about 90° C. Specifically, the hydrophobicfusible carrier may comprise natural or synthetic waxes, fatty alcohols(such as lauryl, myristyl stearyl, cetyl or preferbly cetostearylalcool), fatty acids, including but not limited to fatty acid esters,fatty acid glycerides (mono-, di-, and tri-glycerides), hydrogenatedfats, hydrocarbons, normal waxes, stearic acid, stearyl alcohol andhydrophobic and hydrophilic polymers having hydrocarbon backbones.Suitable waxes include, for example, beeswax, glycowax, castor wax andcarnauba wax. For purposes of the present invention, a wax-likesubstance is defined as any material which is normally solid at roomtemperature and has a melting of from about 30 to about 100° C.

Suitable hydrophobic fusible carrier materials which may be used inaccordance with the present invention include digestible, long chain(C₈₋C₅₀, especially C₁₂-C₄₀), substituted or unsubstituted hydrocarbons,such as fatty acids, fatty alcohols, glyceryl esters of fatty acids,mineral and vegetable oils and natural and synthetic waxes. Hydrocarbonshaving a melting point of between 25° and 90° C. are preferred. Of thelong chain hydrocarbon materials, fatty (aliphatic) alcohols arepreferred in certain embodiments. The oral dosage form may contain up to60% (by weight) of at least one digestible, long chain hydrocarbon.

In addition to the above ingredients, a sustained-release matrix mayalso contain suitable quantities of other materials, e.g., diluents,lubricants, binders, granulating aids, colorants, flavorants andglidants that are conventional in the pharmaceutical art. The quantitiesof these additional materials will be sufficient to provide the desiredeffect to the desired formulation. In addition to the above ingredients,a sustained-release matrix incorporating melt-extruded multiparticulatesmay also contain suitable quantities of other materials, e.g. diluents,lubricants, binders, granulating aids, colorants, flavorants andglildants that are conventional in the pharmaceutical art in amounts upto about 50% by weight of the particulate if desired. Specific examplesof pharmaceutically acceptable carriers and excipients that may be usedto formulate oral dosage forms are described in the Handbook ofPharmaceutical Excipients, American Pharmaceutical Association (1986),incorporated by reference herein.

In order to facilitate the the reparation of a solid, sustained-releaseoral dosage form according to this invention there is provided, in afurther aspect of the present invention, a process for the preparationof a solid, sustained-release oral dosage form according to the presentinvention comprising incorporating opioids or a salt thereof in asustained-release melt-extruded matrix. Incorporation in the matrix maybe effected, for example, blending the opioid analgesic, together withat least one hydrophobic material and preferably the additionalretardantmaterial (hydrophobic fusible carrier) to obtain a homogeneousmixture. The homogeneous mixture is then heated to a temperaturesufficient to at least soften the mixture sufficiently to extrude thesame. The resulting homogeneous mixture is then extruded, e.g., using atwin-screw extruder, to form strands. The extrudate is preferably cooledand cut into multiparticulates by any means known in the art. Theestrands are cooled and cut into multiparticulates. The multiparticulatesare then divided into unit doses. The extrudate preferably has adiameter of from about 0.1 to about 5 mm and provides sustained releaseof the therapeutically active agent for a time period of from about 8 toabout 24 hours.

An optional process for preparing the melt extrusions, multiparticulatesand unit doses of the present invention includes directly metering intoan extruder a water-insoluble retardant, a therapeutically active agent,and an optional binder; heating said homogenous mixture; extruding saidhomogenous mixture to thereby form strands; cooling said strandscontaining said homogencous mixture; and cutting said strands intoparticles having a size from about 0.1 to to about 12 mm; and dividingsaid particles into unit doses. In this aspect of the invention, arelatively continuous manufacturing procedure is realized.

The diameter of the extruder aperture or exit port can also be adjustedto vary the thickness of the extruded strands. Furthermore, the exitpart of the extruder need not be round; it can be oblong, rectangular,etc. The exiting strands can be reduced to particles using a hot wirecutter, guillotine, etc.

The melt extruded multiparticulate system can be, for example, in theform of granules, spheroids or pellets depending uponthe extruder exitorifice. For purposes of the present invention, the terms “melt-extrudedmultiparticulate(s)” and “melt-extruded multiparticulate system(s)” and“melt-extruded particles” shall refer to a plurality of units,preferably within a range of similar size and/or shape and containingone or more active agents and one or more excipients, preferablyincluding a retardant as described herein. In this regard, themelt-extruded multiparticulates will be of a range of from about 0.1 toabout 12 mm in length and have a diameter of from about 0.1 to about 5mm. In adition, it is to be understood that the melt-extrudedmultiparticulates can be any geometricalshape within this size rangesuch as beads, microspheres, seeds, pellets, etc.

A particular advantage provided by the invention is the preparation ofsustained-release melt-extruded multiparticulate formulations which donot require further processing, e.g., the extrudate may simply be cutinto desired lengths and divided into unit doses of the therapeuticallyactive agent without the need of a spheronization step.

In one preferred embodiment, oral dosage forms are prepared to includean effective amount of melt-extruded multiparticulates within a capsule.For example, a plurality of the melt-extruded multiparticulates may beplaced in a gelatin capsule in an amount sufficient to provide aneffective sustained-release dose when ingested and contacted by gastricfluid.

In another perferred embodiment, a suitable amount of themultiparticulate extrudate is compressed into an oral tablet usingconventional tableting equipment using standard techniques. Techniquesand compositions for making tablets (compressed and molded), capsules(hard and soft gelatin) and pills are also described in Remington'sPharmaceutical Sciences, (Arthur Osol, editor), 1553-1593 (1980),incorporated by reference herein.

In yet another preferred embodiment, the extrudate can be shaped intotablets as set forlh in U.S. Pat. No. 4,957,681 (Klimesch, et. al.),describcd in additional detail above and hereby incorporated byreference.

In yet a further embodiment, the extrudate can be shaped intosuppositories containing a unit dose of the therapeutically activeagent. This may be accomplished using techniques and equipment wellknown to those skilled in the art.

Optionally, the sustainedrelease melt-extruded multiparticulate systemsor tablets can be coated, or the gelatin capsule can be further coated,with a sustained-release coating comprising one of the hydrophobicmaterials described above. Such coatings preferably include a sufficientamount of hydrophobic material to obtain a weight gain level from about2 to about 30 percent, although the overcoat may be greater dependingupon the physical properties of the particular opioid analgesic compoundutilized and the desired release rate, among other things. In certainpreferred embodiments of the present invention, the hydrophobic polymercomprising the sustained-release coating is a pharmaceuticallyacceptable acrylic polymer, such as those described hereinabove. Thesolvent which is used for the hydrophobic material in the coating may beany pharmaceutically acceptable solvent, including water, methanol,ethanol, methlyene chloride and mixtures thereof. The unit dosage formsof the present invention may further include combinations ofmelt-extruded multiparticulates containing one or more of thetherapeutically active agents disclosed above before being encapsulated.Furthermore, the unit dosage forms can also include an amount of animmediate release therapeutically active agent for prompt therapeuticeffetc. The immediate release therapeutically active agent may beincorporated, e.g., as separate pellets within a gelatin capsule, or maybe coated on the surface of the compressed tablet which has beenprepared from the multiparticulate extrudate as set forth above.

The controlled-release formulations of the present invention slowlyrelease the therapeutically active agent, e.g., when ingested andexposed to gastric fluids, and then to intestinal fluids. Thecontrolled-release profile of the melt-extruded formulations of theinvention can be altered, for example, by varying the amount ofretardant, i.e., hydrophobic polymer, by varying the amount ofplasticizer relative to hydrophobic polymer, by the inclusion ofadditional ingredients or excipients, by altering the method ofmanufacture, etc. In certain embodiments of the invention, the thesustained-release dosage forms of the present invention preferablyrelease the therapeutically active agent at a rate that is independentof pH, e.g., between pH 1.6 and 7.2. In other embodiments, theformulations can be designed to provide a pH-dependent release of thetherapeutically active agent.

In other embodiments of the invention, the melt extruded material isprepared without the inclusion pf the therapeutically active agent,which is added thereafter to the extrudate. Such formulations typicallywill have the therapeutically active agent blended together with theextruded matrix material, and then the mixture would be tabletted inorder to provide a slow release formulation. Such formulations may beadvantageous, for example, when the therapeutically active agentincluded in the formulation is sensitive to temperatures needed forsoftening the hydrophobic material and/or the retardant material.

In certain preferred embodiments, the invention is directed tosustained-release oral opioid formulations which are administrable on aonce-a-day basis, and which are prepared from the melt extrudatesdescribed herein. Such dosage forms will provide an in-vitro release(when assessed by the USP Paddle or Basket Method at 100 prm at 900 mlaqueouss buffer (pH between 1.6 and 7.2) at 37° C. from about 1 to about42.5% opioid released after one hour, from about 5 to about 65% opioidreleased after 2 hours, from about 15 to about 85% opioid released after4 hours, from about 20 to about 90% opioid released after 6 hours, fromabout 35 to about 95% opioid released after 12 hours, from about 45 toabout 100% opioid released after 18 hours, and from about 55 to about100% opioid released after 24 hours, by weight. Such formulations mayfurther be characterized by a peak plasma level at from about 2 to about8 hours after oral adminitration, and preferably from about 4 to about 6hours after administration. Such formulations are further characterizedby a W₅₀ from about 4 to about 12 hours.

In certain preferred embodiments, the oral 24 hour sustained-releaseopioid dosage form provides a rapid rate of initial rise in the plasmaconcentration of the opioid after oral administration, such that thepeak plasma level obtained in-vivo occurs from about 2 to about 8 hoursafter oral administration, and/or the absorption half-life is from about1 to about 3 hours after oral administration (in the fasted state). Morepreferably in this embodiment the absorption half-life is 1-6 hours andpossibly 1-3 hours after oral administration (in the fasted state). Suchformulations provide an in-vitro dissolution under the conditionsspecified above, from about 12.5 to about 42.5% opioid released afterone hour, from about 25 to about 65% opioid released after 2 hours, fromabout 45 to about 85% opioid released after 4 hours, and greater thanabout 60% opioid released after 8 hours, by weight.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

The following examples illustrate various aspects of the presentinvention. They are not to be construed to limit the claims in anymanner whatsoever.

Melt-Extrusion Techniques

Typlical melt extrusion systems capable of carrying-out the presentinvention include a suitable extruder drive motor having variable speedand constant torque control, start-stop controls, and ammeter. Inadditioin, the system will include a temperature control console whichincludes temperature sensors, cooling means and temperature indicatorsthroughout the length of the extruder. In addition, the system willinclude an extruder such as twin-screw extruder which consists of twocounter-rotating intermeshing screws enclosed within a cylinder orbarrel having an aperture or die at the exit thereof. The feed materialsenter through a feed hopper and is moved through the barrel by thescrews and is forced through the die into strands which are thereafterconveyed such as by a continuous movable belt to allow for cooling andbeing directed to a pelletizer or other suitable device to render theextruded ropes into the multiparticulate system. The pelletizer canconsist of rollers, fixed knife, rotating cutter and the like. Suitableinstruments and systems are available from distributors such as C.W.Brabender Instruments, Inc. of South Hackensack, N.J. Other suitableapparatus will be apparent to those of ordinary skill in the art.

A further aspect of the invention is related to the preparation of meltextruded multiparticulates as set forth) above in a manner whichcontrols the amount of air included in the extruded product. Bycontrolling the amount of air included in the extrudate, it has beensurprisingly found that the release rate of the therapeutically activeagent from the, e.g., multiparticulate extrudate, can be alteredsignificantly. In certain embodiments, it has been surprisingly foundthat the pH dependecy of the extruded product can be altered as well.

Thus, in a further aspect of the invention, the melt extruded product isprepared in a manner which substantially excludes air during theextrusion phase of the process. This may be accomplished, for example,by using a Leistritz extruder having a vacuum attachment. It has beensurprisingly found that extruded multiparticulates prepared according tothe invention using the Leistritz extruder under vacuum provides amelt-extruded product having different physical characteristics. Inparticular, the extrudate is substantially non-porous when magnified,e.g., using a scanning electron microscope whichr provides an SEM(scanning electron micrograph). Contrary to conventional thought, it hasbeen found that such substantially non-porous formulations provide afaster release of the therapeutically active agent, relative to the sameformulation prepared without vacuum. SEMs of the multiparticulatesprepared using an extruder under vacuum appear very smooth, and themultiparticulates tend to be more robust than those multiparticulatesprepared without vacuum. It has been observed that in at least certainformulations, the use of extrusion under vacuum provides an extrudedmultiparticulate product which is more pH-dependent than its counterpartformulation prepared without vacuum.

General Pellet Manufacturing Procedure

The following technique was used to manufacture the extrudate andmultiparticulates for Examples 1-26:

Blend the required amount of drug, hydrophobic material and binder alongwith any additional excipients.

Charge a powder feeder with the proper amount of drug/excipient blend.

Set temperatures of extruder heating zones to the required temperature,depending on the formulation. Typically, the temperature should be setat about 83° C. Wait until the corresponding heating zones reach steadytemperatures. Set the extruder screw rotation speed to 20 rpm. Start thefeeder, the conveyor and the pelletizer. After the excipients are meltedand the drug is embedded in the molten mixture, the resultant viscousmass is extruded as spaghetti-like strands. The diameter of the extruderaperture can be adjusted to vary the thickness of the resulting strand.

Set the conveyor belt speed to an appropriate speed (e.g., 3-100ft/min). Allow the extruded semisolid strands to be congealed and/orhardened while transported to the pelletizer on the conveyor belt.Additional cooling devices may be needed to ensure proper congealing.(The conveyor belt may not be needed to cool the strand, if the materialcongeals rapidly enough.)

Set the roller knife to an appropriate speed (e.g., to 3-100 ft/min and100-800 rpm). Cut the congealed strands to the desired size (e.g., 3-5mm in diameter, 0.3-5 mm in length.

Collect the pellet product.

Fill a desired weight of pellets into hard gelatin capsules to obtain anappropriate doses of the drug.

Dissolution Method

The following dissolution method was used to obtain dissolution profilesfor the dosage forms of Examples 1-25:

(USP II Paddle at 100 rpm at 37° C.)

Media—1st hour in 700 ml simulated gastric fluid (SGF), pH 1.2 withoutenzyme

-   -   thereafter, 900 ml simulated intestinal fluid (SIF), pH 7.5        without enzyme

Using HPLC procedures for assay

The followifg examples illustrate various aspects of the presentinvention. They are not meant to be construed to limit the claims in anymanner whatsoever.

EXAMPLES 1-2 Controlled Release Chlorpheniramine Formulations

In these examples, chlorpheniramine maleate controlled release pelletswere prepared according to the above manufacturingprocedure usingethylcellulose and an acrylic polymer (Eudragit RSPO), respectively asthe retardant. The formulations are set forth in Tables 1 and 2 below.The dissolution of these formulations is set forth in FIG. 1. Drugrelease rate from ethylcellulose pellets (prepared at 105° C.) issignificantly slower than that from Eudragit RSPO pellets (prepared at85° C.). TABLE 1 EX. 1 Composition Amt. (mg) per CapsuleChlorpheniramine Maleate  60 Ethyl Cellulose  84 Stearic Acid  36 Total180

TABLE 2 EX. 2 Composition Amt. (mg) per Capsule Chlorpheniramine Maleate 60 Eudragit RSPO  84 Stearic Acid  36 Total 180

EXAMPLES 3-6 Controlled Release Morphine Formulations

Ex. 3 The excipients used in Ex. 2 were employed to make morphinesulfate controlled release pellets. TABLE 3 EX. 3 Composition Amt. (mg)per Capsule Morphine Sulfate  60 Eudragit RSPO  42 Stearic Acid  18Total 120

The drug release rate of Example 3 was slower than expected especiallyduring later hours of the dissolution.

Ex. 4-5 Examples 4-5 were prepared in accordance with Example 3 above.To increase the drug dissolution rate during later hours, varyingamounts of Eudragit L-100 were incorporated in the formulation. The drugdissolution rate increases with increasing amount of Eudragit L-100 inthe formulation. The morphine sulfate capsule formulation are set forthin tables 4-6 below: TABLE 4 EX. 4 Composition Amt. (mg) per CapsuleMorphine Sulfate 60 Eudragit RSPO 38.4 Eudragit L-100 3.6 Stearic Acid18 Total 120

TABLE 5 EX. 5 Composition Amt. (mg) per Capsule Morphine Sulfate 60Eudragit RSPO 33.6 Eudragit L-100 8.4 Stearic Acid 18 Total 120

Ex. 6. A sustained release morphine sulfate formulation was preparedhaving the ingredients listed in Table 6 below: TABLE 6 PercentageIngredients Amt(mg)/Capsule in Formula Morphine Sulfate  60  50 EudragitRSPO  36  30 Eudragit L-100  6  5 Stearic Acid  18  15 Total 120 100

The formulation of Example 6 was prepared as follows:

Pellet Manufacture

a. Extruder system description—The twin screw extruder is consisted of apair of counterrotating screws and a barrel block equipped withheating/cooling zones. The extrudate is delivered to a pelletizerthrough a conveyor belt and cut into pellets of the desirable size.

b. Manufacturing procedure

-   1. Blend the drug and all the excipients in a proper mixer.-   2. Place the mixture in a powder feeder.-   3. Set temperatures of the extruder heating zones to approximately    83° C.-   4. Set the extruder screw rotation speed to 20 rpm.-   5. Start the feeder, the conveyor and the pelletizer.-   6. After the excipients are melted and the drug embedded in the    molten mixture, the viscous mass is extruded as spaghetti-like    strands.-   7. The extrudate is congealed and hardened while being delivered to    the pelletizer on the conveyor belt.-   8. The roller knife of the pelletizer cuts the strands into pellets    of 1.5 mm in diameter and 1.5 mm in length.

Encapsulation

After the pellets were manufactured, 120 mg of pellets are encapsulatedin size #2 hard gelatin capsules, rendering capules containing 60 mg ofmorphine sufate. These capsules were then tested using the followingdissolution methodology:

The capsules of Example 6 were found to have the following dissolutionresults: Time (hr) 1 2 4 8 12 18 24 Mean % dissolved 16 33 52 72 84 95102

As seen in FIG. 3, the drug dissolution rate obtained from the productof Ex. 3 showed a significant pH dependency. The release rate was slowerin SIF (simulated intestinal fluid) than in SGF (simulated gastricfluid).

In FIG. 4, it can be seen that due to the addition of Eudragit L-100,the drug dissolution rate obtained from Ex. 6 was less pH dependent. Thedrug release rate was faster in SIF during later hours of dissolutionwhich is desirable for complete bioavailability.

EXAMPLES 7-8

As demonstrated in FIG. 5, with proper choice of plasticizers, the drugrelease rate from the formula containing Eudragit L-100 can be reduced.This may be necessary to achieve desirable plasma drug concentrationprofiles after oral administration of the pellets. TABLE 7 EX. 7Composition Amt. (mg) per Capsule Morphine Sulfate 60 Eudragit RSPO 33.6Eudragit L-100 8.4 Stearic Acid 9 Diethyl Phthalate 9 Total 120

TABLE 8 EX. 8 Composition Amt. (mg) per Capsule Morphine Sulfate 60Eudragit RSPO 33.6 Eudragit L-100 8.4 Stearic Acid 9 Tributyl Citrate 9Total 120

EXAMPLES 9-10

A different polymer/wax combination was used as an alternativeformulation. As seen in FIG. 6, the drug dissolution rate fromethylcellulose/polyvinyl acetate phthalate was somewhat faster. TABLE 9EX. 9 Composition Amt. (mg) per Capsule Morphine Sulfate 60 EthylCellulose 38.4 Polyvinyl Acetate Phthalate 3.6 Stearic Acid 18 Total 120

TABLE 10 EX. 10 Composition Amt. (mg) per Capsule Morphine Sulfate 60Ethyl Cellulose 34.8 Polyvinyl Acetate Phthalate 7.2 Stearic Acid 18Total 120

EXAMPLES 11-14 Controlled Release Oxycodone Formulations

The formula used in Ex. 6 was applied to oxycodone hydrochloride. Due tothe higher potency of oxycodone, only 20 mg of drug was used. Themissing 40 mg was replaced by 40 mg of talc (Ex. 12). No replacement wasused in Ex. 11. When tested in only SGF or SIF, the use of Eudragit Lcauses the formulation to become less pH dependent. The results areshown in FIG. 7. TABLE 11 Percentage Ingredients Amt(mg)/Capsule inFormula Oxycodone HCL 20 25 Eudragit RSPO 36 45 Eudragit L-100 6 7.5Stearic Acid 18 22.5 Total 80 100

The pellet manufacturing procedure and the dissolution method are thesame as described in Example 6.

The above capsules were found to have the dissolution results set forthin Table 11a below: TABLE 11a Time (hr) 1 2 4 8 12 18 24 Mean %dissolved 14 29 45 66 81 94 101

TABLE 12 EX. 12 Composition Amt. (mg) per Capsule OxycodoneHydrochloride 20 Eudragit RSPO 36 Eudragit L-100 6 Stearic Acid 18 Talc40 Total 120

Ex. 13 Oxycodone HCl once-a-day capsules were produced with thefollowing formula using the technology describced in Example 6. Theformulation is set forth in Table 13 below. TABLE 13 PercentageIngredients Amt(mg)/Capsule in Formula Oxycodone HCl 20 25 Eudragit RSPO39 48.75 Eudragit L-100 3 3.75 Stearic Acid 18 22.5 Total 80 100

The pellet manufacturing procedure is the same as described in Example6. However, 80 mg of pellets were encapsulated to contain 20 mg ofoxycodone HCL.

The above capsules were tested using the following dissolutionmethodology:

-   1. Apparatus—USP type II (paddle), 100 rpm at 37° C.-   2. Media—Either 900 ml simulated gastric fluid (SGF), pH 1.2 without    enzyme; or 900 ml simulated intestinal fluid (SIF), pH 7.5 without    enzyme.-   3. Analytical method—High performance liquid chromatography.

The dissolution results are set forth in Table 13a below: TABLE 13a Time(hr) 1 2 4 8 12 18 24 Mean % dissolved (SGF) 13 20 29 41 51 62 71 Mean %dissolved (SIF) 14 21 31 44 57 68 80

Ex. 14 To prepare an oxycodone HCl controlled release tablet which woulddissolve preferentially in a lower pH, the following formula is used:TABLE 14 Ingredients Amt(mg)/Tablet Percentage in Formula Oxycodone HCl40 30.8 Eudragit RS30D (solid) 14 10.8 Spray Dried Lactose 35.25 27.1PVP 5 3.9 Triacetin 2 1.5 Stearyl Alcohol 25 19.2 Talc 2.5 1.9 MagnesiumStearate 1.25 0.9 Film Coat 5 3.9 Total 130 100

Total Manufacture

-   1. Mix Eudragit RS30D (suspension) and Triacetin for 5 minutes.-   2. Place spray dried lactose, oxycodone HCl, PVP, in a fluid bed    drier.-   3. Spray the ssuspension onto the powders under fluidization.-   4. Pass the granulation through a Comil to reduce lumps.-   5. Melt stearyl alcohol at 70° C.-   6. Incorporate the molten stearyl alcohol into the dry granulation    in a Collete Mixer.-   7. Transfer the waxed granulation to a cooling tray and allow the    granulation to congeal.-   8. Pass the granulation through a Comil.-   9. Mix the waxed granulation with talc and magnesium stearate in a    Collete Mixer.-   10. Compress the lubricated granulation into tablets using a rotary    tablet press.-   11. Film coat the tablets.

These tablets were then tested using the following dissolutionmethodology described in Example 13.

The above tablets were found to have the following dissolution results:TABLE 14a Time (hr) 1 2 4 8 12 Mean % dissolved SGF 39 53 70 90 99 Mean% dissolved SIF 35 48 65 83 93

EXAMPLES 15-19 Controlled Release Hydromorphone Formulations

Ex. 15-16 The formula used in Ex. 6 was applied to hydromorphonehydrochloride. Due to the higher potency of hydromorphone, only 8 mg ofdrug was used. The missing 52 mg was replaced by 52 mg of talc (Ex. 16)or 52 mg of excipients (Ex. 15). The results are shown in FIG. 8. TABLE15 EX. 15 Composition Amt. (mg) per Capsule Hydromorphone Hydrochloride8 Eudragit RSPO 67.2 Eudragit L-100 11.2 Stearic Acid 33.6 Total 120

TABLE 16 EX. 16 Composition Amt. (mg) per Capsule HydromorphoneHydrochloride 8 Eudragit RSPO 36 Eudragit L-100 6 Stearic Acid 18 Talc52 Total 120

Ex. 17 1 Hydromorphone HCl once-a-day capsules were produced with theformula set forth in Table 17 below using the technology described inExample 6. TABLE 17 Percentage Ingredients Amt(mg)/Capsule in FormulaHydromorphone HCL 8 10 Eudragit RSPO 53 66.25 Stearyl Alcohol 19 23.75Total 80 100

The pellet manufacturing procedure is the same as described in Example6. However, pellets of 1.0 mm in diameter and 1.0 mm in length wereprepared. Each capsule holds 80 mg of pellets and contains 8 mg ofhydromorphone HCL.

The above capsules were tested using the dissolution methodologydescribed in Example 6.

The above capsules were found to have the dissolution results set forthin Table 17a below: TABLE 17a Time (hr) 1 2 4 8 12 18 24 Mean %dissolved 17 28 32 45 56 69 82

Ex. 18 Hydromorphone HCl once-a-day capsules were produced with theformula set forth in 18 below as the second example of the technologydescribed in Example 6. TABLE 18 Percentage Ingredients Amt(mg)/Capsulein Formula Hydromorphone HCl 8 10 Eudragit RSPO 48 60 Stearyl Alcohol 2430 Total 80 100

The pellet manufacturing procedure and the dissolution method are thesame as described in Example 6.

The above capsules were found to have the dissolution results set forthin Table 18a below: TABLE 18a Time (hr) 1 2 4 8 12 18 24 Mean %dissolved 23 29 40 56 69 84 96

Ex. 19 Hydromorphone HCl once-a-day capsules were produced with thefollowing formula according to the method described Example 6. TABLE 19Percentage Ingredients Amt(mg)/Capsule in Formula Hydromorphone HCL 8 10Eudragit RSPO 41.5 51.9 Eudragit L-100 8.5 10.6 Stearic Acid 22 27.5Total 80 100

The manufacturing procedure of the pellets and the dissolution methodare the same as described in Example 6.

The above capsules were found to have the following dissolution results.TABLE 19a Time (hr) 1 2 4 8 12 18 24 Mean % dissolved 4 14 36 52 64 7584

EXAMPLE 20

In this Example, a bioavailability study was undertaken. Fourteensubjects were given the morphine sulfate formulations of Example 3. Theresults are provided in Table 20 below in FIG. 10. TABLE 20 Group AUCCmax Tmax Example 3 Fasted 230 15.7 2.1 Example 3 Fed 213 14.0 3.2

From the above data, it can be seen that the formulation is an idealcandidate for an extended release or once-a-day product without a foodeffect.

EXAMPLE 21 Bioavailability of Morphine Sulfate Melt ExtrusiuonMultiparticulate 60 Mg Capsules

A bioavailability study of morphine capsules of Example 6 was conductedin 12 normal male volunteers. Capsules of 60 mg in strength wereadministered either with or without food in a single dose, two-waycrossover study. Blood samples were taken periodically and assayed formorphine concentrations using gas chromatography with mass detection(G/MS). From the data, the following pharmacokinetic parameters werecalculated and are indicated in Table 21 below. TABLE 21 AUC, Treatmentn · hr/ml Cmax, n/ml Tmax, hr Fasted 228 15.7 2.1 Fed 210 14.0 3.2

When compared to the typical blood levels of MS Contin®, a single dosetwice-a-day marketed morphine sulfate 30 mg tablets, in the fastedstate, it can be ssen that the capsules of Example 6 are suitable foronce daily administration. At the 24th hour the blood levels are wellabove MS-Contin and within the therapeutic range (FIG. 11).

EXAMPLE 22 Bioavailability of OXY-MEM 20 Mg Capsules

A bioavailability study of oxycodone capsules of examples 11 and 13 wasconducted in 10 normal male volunteers. Capsules of example 13 wereadministered either with ot without food. Capsules of example 11 wereadministered without food. The study was conducted in a single dose,four-way crossover design. Blood samples were taken periodically andassayed for oxycodone concentrations using gas chromatography with massdetection (G/MS).

From the data, the following pharmacokinetic parameters were calculatedas set forth in Table 22 below: TABLE 22 AUC, Treatment n · hr/ml Cmax,n/ml Tmax, hr Example 13, fasted 207 9.7 5.3 Example 13, fed 261 14.86.4 Example 11, fasted 244 12.9 6.0 Oxycontin, fasted 249 20.8 3.2

From the above data, it can be concluded that both Examples 11 and 13,but particularly Example 13, are suitable for once daily administration.This is shown graphically in FIG. 12.

EXAMPLE 23 Bioavailability of Example 14 Tablets

A bioavailability study of oxycodone controlled release tablets ofexample 14 was conducted in 25 normal volunteers. These tablets wereadministered either with or without foo. The study was conducted in asingle dose, randomized crossover design. Blood samples were takenperiodically and assayed for oxycodone concentrations using gaschromatography with mass detection (GC/MS). The plasma oxycodoneconcentration versus time curves are shown in FIG. 13.

From the data, the following pharmacokinetic parameters were calculated.TABLE 23 Treatment AUC, ng · hr/ml Cmax, ng/ml Tmax, hr Example 14,fasted 422 39.3 3.1 Example 14, fed 416 35.3 4.8

Surprisingly, it was found that the controlled release oxycodone HClpreparation, which dissolved preferentially in low pH, does not showsubstantial food effect. From the Cmax data, it can be seen that thereis no significant change in blood oxycodone levels when the drug wastaken with food than without food (35.3/39.3=0.09). From the AUC (areaunder the curve) data, it appears that the amount of drug absorbed withor without food is similar (416/422=0.986).

EXAMPLE 24 Bioavailability of HH-MEM 8 Mg Capsules

A bioavailability study of hydromorphone capsules of Examples 17 and 18was conducted using a single dose, five-way crossover study in 12 normalmale volunteers. The subjects received either 8 mg of Dilaudid tablet(immediate release) or 8 mg of HH-MEM capsules. Dilaudid tablets wereadministered after an overnight fast. MEM capsules were administeredwith or without food. Blood samples were taken periodically and assayedfor hydromorphone concentrations using gas chromatography with massdetection (G/MS). From the data, the following pharmacokineticparameters were calculated. TABLE 24 AUC, Treatment n · hr/ml Cmax, n/mlTmax, hr Example 17, fasted 19.00 0.72 6.8 Example 17, fed 20.10 0.752.4 Example 18, fasted 19.23 0.76 3.9 Example 18, fed 21.47 0.93 1.9Dilaudid, fasted 14.55 3.69 0.7

From the data, both formulations 17 and 18 would be suitable foronce-a-day administration both not having a food effect, and in factExample 17 looks ideal. The data of Example 17 is shown graphically inFIG. 14 and the data of Example 18 is shown graphically in FIG. 15.

EXAMPLE 25 Steady State Bioavailability of HH-MEM 8 Mg Capsules

To assess steady state plasma levels and the effect of food onhydromorphone, a single dose, two-way crossover study was conducted in12 normal male volunteers. The subjects received either 4 mg of Dilaudid(immediate release) every 6 hours or 16 mg of the capsules according toExample 17 every 24 hours. Venous blood samples were taken atpredetermined time points. The plasma hydromorphone concentrations werequantitated using gas chromatography with mass detection (G/MS).

From the data from day 4, the following pharmacokinetic parameters werecalculated and set forth in Table 25 below. TABLE 25 AUC, Cmax,Treatment n · hr/ml n/ml Cmin, n/ml Tmax, hr Example 17 36.08 2.15 1.495.8 Dilaudid 33.53 3.44 0.94 1.6

The results are shown graphically in FIG. 16. From this data it can beseen that Example 17 is an ideal product for once-a-day administrationfor either single dose or multiple dose administration.

EXAMPLE 26 Bioavailability of HH-MEM 8 Mg capsules

To assess bioavailability and effect of food on hydromorphone MEMcapsules, a single dose. three-way crossover study was conducted in 12normal male volunteers. The subjects received either 8 mg of Dilaudidtablet *immediate release) or 8 mg of HH-MEM (Example 19) Dilaudidtablets were administered after an overnight fast. MEM capsules wereadministered with our without food. Venous blood samples were taken atpredetermined at time points. The plasma hydromorphone concentrationswere quantitated using gas chromatography with mass detection (G/MS).

From the data, the following pharmacokinetic parameters were calculatedand are st forth in Table 26 below. TABLE 26 AUC, Cmax, Treatment n ·hr/ml n/ml Tmax, hr Example 19, fasted 15.83 0.52 5.6 Example 19, fed16.55 0.65 4.1 Dilaudid, fasted 16.54 3.15 0.8

From the above data it can be cconcluded that a once-a-day Hydromorphoneproduct can be produced using other ingredients than are used forExamples 17 and 18. This data is shown graphically in FIG. 17.

EXAMPLE 27 Tramadol HCl 200 Mg SR Tablet

The following formula is used to prepare melt extrusion granulation andtablet. TABLE 27 Percentage Ingredients Amt(mg)/Tablet in FormulaTramadol HCl 200 53.4 Eudragit RSPO 74 19.8 Tributyl Citrate 14.8 4.0Stearyl Alcohol 74 19.8 Talc 7.4 2.0 Magnesium Stearate 3.8 1.0 Total374 100

Granulation Manufacture

a. Extruder system description—The twin screw extruder is consisted of apair of counterrotating screws and a barrel block equipped withheating/cooling zones. The stranded extrudate is congealed on a conveyorbelt and cut into pellets of the desirable size.

b. Manufacturing procedure

-   1. Blend the drug and all the excipients in a proper mixer.-   2. Place the mixture in a powder feeder.-   3. Set temperatures of the extruder heating zones to approximately    65° C.-   4. Set the extruder screw rotation speed to 40 rpm.-   5. Start the feeder and the conveyor.-   6. After the excipients are melted and the drug embedded in the    molten mixture, the viscous mass is extruded as spaghetti-like    strands.-   7. The extrudate is congealed and hardened while being carried away    on a conveyor belt.-   8. The stranded extrudate was cut into pellets of 2 mm in diameter    and 2-8 cm in length.

Tableting

The pellets were milled into granules through a suitable screen. Thegranulation was blended with talc and magnesium stearate. The mixturewas then compressed into capsule-shaped tablets.

Dissolution Method

-   1. Apparatus—USP Type II (paddle), 100 rpm at 37° C.-   2. The tablet was placed in a tablet sinker clip and immersed in    each vessel.-   3. Media—900 ml pH 6.5 phosphate buffer.-   4. Analytical method—High performance liquid chromatography.

The above tablets were found to have the following dissolution results:TABLE 27a Time (hr) 1 2 4 8 12 18 24 Mean % dissolved 24 33 45 61 71 8288

EXAMPLE 28 Tramadol HCl 200 Mg SR Tablet

The following formula is used to prepare melt extrusion granulation andtablet with a slower dissolution profile than Example 27. TABLE 28Percentage Ingredients Amt(mg)/Tablet in Formula Tramadol HCl 200 44.1Ethyl cellulose 110 24.3 Tributyl Citrate 22 4.9 Stearyl Alcohol 11014.3 Talc 7.4 1.6 Magnesium Stearate 3.4 0.8 Total 453.2 100

The manufacturing method and dissolution method are the same asdescribed in Example 27. Additional dissolution media used include pH1.2 simulated gastric fluid (SGF) without enzyme, pH 7.5 simulatedintestinal fluid (SIF) without enzyme, and pH 4 phosphate buffer.

The above tablets were found to have the following dissolution results:TABLE 28a Time (hr) 1 2 4 8 12 18 24 Mean % dissolved SGF 18 26 35 49 5970 80 pH4 17 25 34 49 60 73 83 pH6.5 17 23 33 46 57 70 81 SIF 17 23 3245 56 68 78

The results show that the dissolution profiles of Tramadol SR tablets inmedia of different pH values are similar. Based on our experience withsimilar formula of other opiates, a formula which demonstrates pHindependent dissolution profile would provide a consistent drug releaseprofile in vivo without food effect.

The examples provided above are not meant to be exclusive. Many othervariations of the present invention would be obvious to those skilled inthe art, and are contemplated to be within the scope of the appendedclaims.

1. A sustained-release pharmaceutical formulation, comprising amelt-extruded blend of a therapeutically active agent, one or morehydrophobic materials selected from the group consisting ofalkylcelluloses, acrylic and methacrylic acid polylners and copolrmers,shellac, zein, hydrogenated castor oil, hydrogenated vegetable oil, andmixtures thereof; and one or more hydrophobic fusible carriers whichprovide a further retardant effect and selected from the groupconsisting of natural or synthetic waxes, fatty acids, fatty alcohols,and mixtures thereof, said hydrophobic fusible carrier having a meltingpoint from 30 to 200° C., said melt-extruded blend divided into a unitdose containing an effective amount of said therapeutically active agentto render a desired therapeutic effect and providing a sustained-releaseof said therapeutically active agent for a time period of from about 8to about 24 hours.
 2. The formulation of claim 1, wherein said extrudatecomprises a strand-shaped matrix cut into into multiparticulates havinga length of from about 0.1 to about 5 mm in length.
 3. The formulationof claim 1, wherein said extrudate has a diameter of from about 0.1 toabout 5 mm.
 4. The formulation of claim 1, wherein said therapeuticallyactive agent is an opioid analgesic.
 5. The formulation of claim 4,wherein said opioid analgesic is selected from the group consisting ofalfentanil, allylprodine, alphaprodine, anileridine, benzylmorphine,bezitramide, buprenorphine, butorphanol, clonitazene, codeine,cyclazocine, desomorphine, dextromoramide, dezocine, diampromide,dihydrocodeine, dihydromorphine, dimenoxadol, dimepheptanol,dimethylthiambutene, dioxaphetyl butyrate, dipipanone, eptazocine,ethoheptazine, ethylmethylthiambutene, ethylmorphine, etonitazene,fentanyl, heroin, hydrocodone, hydromorphone, hydroxypethidine,isomethadone, ketobemidone, levallorphan, levorphanol, levophenacylmorphan, lofentanil, meperidine, meptazinol, metazocine, methadone,metopon, morphine, myrophine, nalbuphine, narceine, nicomorphine,norlevorphanol, normethadone, nalorphine, normorphine, norpipanone,opium, oxycodone, oxymorphone, papaveretum, pentazocine, phenadoxone,phenomorphan, phenazocine, phenoperidine, piminodine, piritramide,propheptazine, promedol, properidine, propiram, propoxyphene,sufentanil, tramadol, tilidine, salts thereof and mixtures thereof. 6.The extrudate of claim 1, wherein said opioid analgesic is selected fromthe group consisting of morphine, codeine, hydromorphone, hydrocodone,oxycodone, oxymorphone, dihydrocodeine, dihydromorphine tramadol andmixtures thereof.
 7. The formulation of claim 2, wherein a unit dosecomprising an effective amount of said multiparticulates to render atherapeutic effect is contained within a gelatin capsule.
 8. Theformulation of claim 2, wherein a unit dose comprising an effectiveamount of said multiparticulates to render a therapeutic effect iscompressed into a tablet.
 9. The formulation of claim 8, wherein saidtherapeutically active agent is tramadol.
 10. The formulation of claim 7wherein said therapeutically active agent is an opioid analgesicselected from the group consisting of morphine, codeine, hydromorphone,hydrocodone, oxycodone, oxymorphone dihydrocodeine, dihydromorphine,tramadol and mixtures thereof.
 11. The formulation of claim 10, whichprovides an in-vitro release (when assessed by the USP Paddle or BasketMethod at 100 prm at 900 ml aqueous buffer (pH between 1.6 and 7.2) at37° C. from about 1 to about 42.5% opioid released after one hour, fromabout 5 to about 65% opioid released after 2 hours, from about 15 toabout 85% opioid released after 4 hours, from about 20 to about 90%opioid released after 6 hours, from about 35 to about 95% opioidreleased after 12 hours, from about 45 to about 100% opioid releasedafter 18 hours, and from about 55 to about 100% opioid released after 24hours, by weight.
 12. The formulation of claim 10, which provides a peakplasma level at from about 2 to about 8 hours after oral administration,and preferably from about 4 to about 6 hours after administration. 13.The formulation of claim 10, which provides a W₅₀ from about 4 to about12 hours.
 14. The formulation of claim 10, which provides a rapid rateof initial rise in the plasma concentration of the opioid after oraladministration, such that the peak plasma level obtained in-vivo occursfrom about 2 to about 8 hours after oral administration.
 15. Theformulation of claim 10, which provides a rapid rate of initial rise inthe plasma concentration of the opioid after oral administration, suchthat the absorption half-life is from about 1 to 8 hours after oraladministration (in the fasted state).
 16. The formulation of claim 10,which provides an in-vitro release (when assessed by the USP Paddle orBasket Method at 100 arm it 900 ml aqueous buffer (pH between 1.6 and7.2) at 37° C. from about 12.5 to about 42.5% opioid released after onehour, from about 25 to about 65% opioid released after 2 hours, fromabout 45 to about 85% opioid released after 4 hours, and greater thanabout 60% opioid released after 8 hours, by weight.
 17. The formulationof claim 1, wjerein said extruded blend is substantially non-porous. 18.A method of preparing a sustained-release pharmaceutical extrudatesuitable for oral administration, comprising: blending a therapeuticallyactive agent together with (1) a hydrophobic material selected from thegroup consisting of alkylcelluloses, acrylic and methacrylic acidpolymers and copolymers, shellac, zein, hydrogenated castor oil,hydrogenated vegetable oil, and mixtures thereof and (2) a hydrophobicfusible carrier selected from the group consisting of natural orsynthetic waxes, fatty acids, fatty alcohols, and mixtures thereof, saidretardant material having a melting point between 30-200° C. and beingincluded in an amount sufficient to further slow the release of thetherapeutically active agent, heating said blend to a temperaturesufficient to soften the mixture sufficiently to extrude the same;extruding said heated mixture as a strand having a diameter of from0.1-3 mm; cooling said strand; and dividing said strand to formnon-spheroidal multi-particulates of said extrudate having a length from0.1-5 mm; and dividing said non-spheroidal multi-particulates into unitdoses containing an effective amount of said therapeutically activeagent, said unit dose providing a sustained-release of saidtherapeutically active agent for a time period of from about 8 to about24 hours.
 19. The method of claim 18, wherein said therapeuticallyactive agent is an opioid analgesic is selected from the groupconsisting of alfentanil, allylprodine, alphaprodine, anileridine,benzylmorphine, bezitramide, buprenorphine, butorphanol, clonitazene,codeine, cyclazocine, desomorphine, dextromoramide, dezocine,diampromide, dihydrocodeine, dihydromorphine, dimenoxadol,dimepheptanol, dimethylthiambutene, dioxaphetyl butyrate, dipipanone,eptazocine, ethoheptazine, ethylmethylthiambutene, ethylmorphine,etonitazene, fentanyl, heroin, hydrocodone, hydromorphone,hydroxypethidine, isomethadone, ketobemidone, levallorphan, levorphanol,levophenacyl morphan, lofentanil, meperidine, meptazinol, metazocine,methadone, metopon, morphine, myrophine, nalbuphine, narceine,nicomorphine, norlevorphanol, normethadone, nalorphine, normorphine,norpipanone, opium, oxycodone, oxymorphone, papaveretum, pentazocine,phenadoxone, phenomorphan, phenazocine, phenoperidine, piminodine,piritramide, propheptazine, promedol, properidine, propiram,propoxyphene, sufentanil, tramadol, tilidine, salts thereof and mixturesthereof.
 20. The method of claim 18, further comprising containing saidunit dose of said multiparticulates with a gelatine capsule.
 21. Themethod of claim 18, further comprising compressing said unit dose ofmulti-particulates into a tablet.
 22. The method of claim 18m furthercomprising extruding said heated mixture under vacuum conditions toprovide a substantially non-porous extrudate.
 23. A sustained-releasepharmaceutical formulation, comprising a melt-extruded blend of anopioid analgesic and one or more hydrophobic materials selected from thegroup consisting of alkylcelluloses, acrylic and methacrylic acidpolymers and copolymers, shellac, zein, hydrogenated castor oil,hydrogenated vegetable oil, and mixtures thereof; said melt-extrudedblend divided into a unit dose containing an effective amount of saidtherapeutically active agent to render a desired therapeutic effect andproviding a sustained-release of said therapeutically active agent for atime period of from about 8 to about 24 hours.
 24. The extrudate ofclaim 23, wherein said opioid analgesic is selected from the groupsconsisting of morphine, codeine, hydromorphone, hydrocodone, oxycodone,oxymorphone, dihydrocodeine, dihydromorphine, tramadol and mixturesthereof.